Case Report
Spontaneous tumour lysis syndrome with follicular lymphoma Tumour lysis syndrome describes the metabolic derangement that occurs with tumour breakdown following the initiation of cytotoxic chemotherapy. Typical biochemical findings of tumour lysis syndrome are hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia and/or azotaemia secondary to a rapid breakdown of tumour cells. While tumour lysis syndrome most often occurs after the initiation of chemotherapy in patients with highly proliferative tumours and high tumour burden, spontaneous tumour lysis syndrome has also been reported. This article reports a case of spontaneous tumour lysis syndrome associated with follicular lymphoma, which is generally considered to be an indolent lymphoma.
Discussion
Tumour lysis syndrome is a collection of metabolic and electrolyte disturbances that can be observed during the destruction of tumour cells. Patients at the highest risk of acute tumour lysis syndrome are those who have a large tumour burden or rapidly proliferating tumours (Drakos et al, 1994; Davidson et al, 2004). The incidence of tumour lysis syndrome during the treatment of haematological malignant disease is reported to be between 4 and 42% (Coiffier et al, 2008). While commonly seen after treatment, spontaneous occurrence has also been reported among patients with haeDr Song-Ee Park is Physician, Dr Changwon Choi is Physician, Dr Min-suk Kwon is Physician and Dr Jae-hyun Tae is Physician and Professor Hee-Jun Kim is Associate Professor in the Department of Internal Medicine, Division of Hematooncology, Chung-Ang University College of Medicine, 224-1 Heukseok-dong, Dongjakgu, Seoul, Korea Correspondence to: Professor HJ Kim ([email protected])
172
matological malignant diseases, although this is very rare (Jasek and Day, 1994). Because of its rarity, the incidence of spontaneous tumour lysis syndrome is not known (Hsu et al, 2004). The criteria for definition of tumour lysis syndrome proposed by Cairo and Bishop (2004) were met in this case. Acute tumour lysis syndrome is commonly associated with highly aggressive, bulky lymphoma with high tumour burden. Therefore an aggressive rapidly proliferating lymphoma was initially suspected based on the presentation. In contrast, the final diagnosis was follicular lymphoma, which is considered to be an indolent B-cell lymphoproliferative disorder. The prognosis of follicular lymphoma remains mixed; some patients are asymptomatic for many years, while others may rapidly present with a life-threatening
disease. The patient was classified as low risk of death in follicular lymphoma by the follicular lymphoma international prognostic index (FLIPI) or FLIPI 2 (Federico et al, 2009) because she had one adverse factor (FLIPI: stage IV, FLIPI 2: bone marrow involvement). Meanwhile, the elevated level of serumsoluble interleukin-2 receptor (sIL-2R) found in this patient suggests poor prognosis. A high sIL-2R level has been associated with poor prognosis in non-Hodgkin lymphoma (Jo et al, 2010). Yoshizato et al (2013) showed that sIL-2R correlated with clinical stages, numbers of nodal regions, clinical outcomes and response to treatment. To the best of the authors’ knowledge, this is the first case reporting spontaneous tumour lysis syndrome in a patient with follicular lymphoma. The aetiology of spontaneous tumour lysis syndrome is
Case Report
A 56-year-old woman with no specific past medical history except hypertension was admitted to the authors’ centre with a 3-week history of fatigue, lethargy, decreased appetite and vague abdominal pain. She had lost 5 kg during this period. Physical examination revealed stable vital signs, enlargement of neck and axillary lymph nodes, and splenomegaly. Computed tomography scan showed systemic lymphadenopathy and a 5.8 cm adrenal homogenous mass. 18F-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography showed 18F-fluoro-2-deoxy-D-glucose uptake in multiple lymph nodes and the adrenal mass (Figure 1). Laboratory work showed severe metabolic derangements: serum urea nitrogen 68 mg/dl (normal 6–21 mg/dl), potassium 6.2 mmol/litre (normal 3.6–5.2 mmol/litre), creatinine 3.4 mg/dl (normal 0.6–1.1 mg/dl), lactate dehydrogenase 150 IU/litre (normal 122–222 IU/litre), uric acid 12.5 mg/dl (normal 2.7–6.1 mg/dl), ionized calcium 3.71 mg/ dl (normal 4.80–5.70 mg/dl) and phosphate 6.9 mg/dl (normal 2.5–4.5 mg/dl). An arterial blood gas analysis showed a pH of 7.19, PCO2 2.3 mmHg, PO2 17.0 mmHg and bicarbonate 5.5 mmol/litre. A presumptive diagnosis of lymphoma with spontaneous tumour lysis syndrome was made. After aggressive treatment with intravenous hydration and furosemide, laboratory abnormalities dramatically improved over the next 24 hours. An axillary lymph node biopsy exhibited follicular lymphoma, grade 3, ultimately found to be stage IV (Figure 2). There was also follicular lymphoma in the bone marrow. Additional laboratory data included beta-2 microglobulin 1.4 mg/litre (normal 0.8–2.2 mg/litre) and serum-soluble interleukin-2 receptor (sIL-2R) level 2180 U/ml (range 195–12 520 U/ml). The patient subsequently underwent chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). There was no recurrence of tumour lysis syndrome after chemotherapy. Metabolic complete remission was achieved after two cycles of R-CHOP, and the patient remained progression free for 28 months after completing six cycles.
© 2015 MA Healthcare Ltd
Introduction
British Journal of Hospital Medicine, March 2015, Vol 76, No 3
itish Journal of Hospital Medicine. Downloaded from magonlinelibrary.com by 139.080.123.044 on July 29, 2015. For personal use only. No other uses without permission. . All rights reserve
Case Report indolent malignancy should also be suspected in clinical cases of spontaneous tumour lysis syndrome. BJHM This research was supported by a Chung-Ang University Research Grant. Professor Kim receives institutional research support from Chung-Ang University.
Figure 1. a. Initial computed tomography scan showing a right adrenal homogeneous solid mass (5.8 cm, arrow) and multiple lymph node enlargements in the left para-aortic space (arrow head). b. Initial 18F-fluoro-2-deoxy-D-glucose positron emission tomography scan showing hypermetabolic lesion in right adrenal mass (maximum SUV 14.9).
© 2015 MA Healthcare Ltd
Figure 2. Microscopic finding of follicular lymphoma. a. The lymph node shows atypical follicular structures without germinal centre (haematoxylin and eosin stain x100). b. Immunostain for Bcl-2 shows diffuse, strong positive reaction in the follicular structures (x100).
unclear. Considering conventional risk factors for tumour lysis syndrome, the burden of tumour may have been an important factor in this case. The possibility of a histological transformation to a high grade lymphoma should be considered. The annual risk of transformation of follicular lymphoma is 3% continuing without plateau beyond 15 years (Al-Tourah et al, 2008). While node biopsy showed only follicular lymphoma, it is reasonable to assume that there could have been unseen partial transformation. However, this seems unlikely because of several factors: normal plasma lactate dehydrogenase and ionized calcium levels, no evidence of transformation on bone marrow examination, and the benign clinical course, which is uncommon in highgrade transformation.
Conclusions
This article reports an unusual case in which spontaneous tumour lysis syndrome was the initial presentation of follicular lymphoma. It should be noted that spontaneous tumour lysis syndrome may happen in follicular lymphoma with a large tumour volume and low risk prognostic factors. Although uncommon,
Al-Tourah AJ, Gill KK, Chhanabhai M et al (2008) Population-based analysis of incidence and outcome of transformed non-Hodgkin's lymphoma. J Clin Oncol 26: 5165–9 (doi: 10.1200/jco.2008.16.0283) Cairo MS, Bishop M (2004) Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127: 3–11 (doi: 10.1111/j.1365-2141.2004.05094) Coiffier B, Altman A, Pui CH, Younes A, Cairo MS (2008) Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26: 2767–78 (doi: 10.1200/jco.2007.15.0177) Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, Schreiber MJ (2004) Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med 116: 546–54 (doi: 10.1016/j.amjmed.2003.09.045) Drakos P, Bar-Ziv J, Catane R (1994) Tumor lysis syndrome in nonhematologic malignancies. Report of a case and review of the literature. Am J Clin Oncol 17: 502–5 (doi: 10.1097/00000421199412000-00010) Federico M, Bellei M, Marcheselli L et al (2009) Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 27: 4555–62 (doi: 10.1200/ jco.2008.21.3991) Hsu HH, Chan YL, Huang CC (2004) Acute spontaneous tumor lysis presenting with hyperuricemic acute renal failure: clinical features and therapeutic approach. J Nephrol 17: 50–6 (doi: 10.1007/bf02983533) Jasek AM, Day HJ (1994) Acute spontaneous tumor lysis syndrome. Am J Hematol 47: 129–31 (doi: 10.1002/ajh.2830470212) Jo SA, Hwang SH, Chang CL et al (2010) Clinical relevance of elevated levels of serum soluble interleukin-2 receptor alpha (sIL-2Ralpha) in patients with non-Hodgkin's lymphoma. Korean J Lab Med 30: 600–5 (doi: 10.3343/ kjlm.2010.30.6.600) Yoshizato T, Nannya Y, Imai Y, Ichikawa M, Kurokawa M (2013) Clinical significance of serum-soluble interleukin-2 receptor in patients with follicular lymphoma. Clin Lymphoma Myeloma Leuk 13: 410–16 (doi: 10.1016/j. clml.2013.03.014)
LEARNING POINTS n Biochemical findings which indicate tumour lysis syndrome are hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia and/or azotaemia secondary to a rapid breakdown of tumour cells. n Acute tumour lysis syndrome is commonly associated with highly aggressive, bulky lymphoma with high tumour burden. n Although rare and low risk, indolent follicular lymphoma is a clinically relevant cause of spontaneous tumour lysis syndrome.
British Journal of Hospital Medicine, March 2015, Vol 76, No 3
173
itish Journal of Hospital Medicine. Downloaded from magonlinelibrary.com by 139.080.123.044 on July 29, 2015. For personal use only. No other uses without permission. . All rights reserve
Spontaneous tumour lysis syndrome with follicular lymphoma Tumour lysis syndrome describes the metabolic derangement that occurs with tumour breakdown following the initiation of cytotoxic chemotherapy. Typical biochemical findings of tumour lysis syndrome are hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia and/or azotaemia secondary to a rapid breakdown of tumour cells. While tumour lysis syndrome most often occurs after the initiation of chemotherapy in patients with highly proliferative tumours and high tumour burden, spontaneous tumour lysis syndrome has also been reported. This article reports a case of spontaneous tumour lysis syndrome associated with follicular lymphoma, which is generally considered to be an indolent lymphoma.
Discussion
Tumour lysis syndrome is a collection of metabolic and electrolyte disturbances that can be observed during the destruction of tumour cells. Patients at the highest risk of acute tumour lysis syndrome are those who have a large tumour burden or rapidly proliferating tumours (Drakos et al, 1994; Davidson et al, 2004). The incidence of tumour lysis syndrome during the treatment of haematological malignant disease is reported to be between 4 and 42% (Coiffier et al, 2008). While commonly seen after treatment, spontaneous occurrence has also been reported among patients with haeDr Song-Ee Park is Physician, Dr Changwon Choi is Physician, Dr Min-suk Kwon is Physician and Dr Jae-hyun Tae is Physician and Professor Hee-Jun Kim is Associate Professor in the Department of Internal Medicine, Division of Hematooncology, Chung-Ang University College of Medicine, 224-1 Heukseok-dong, Dongjakgu, Seoul, Korea Correspondence to: Professor HJ Kim ([email protected])
172
matological malignant diseases, although this is very rare (Jasek and Day, 1994). Because of its rarity, the incidence of spontaneous tumour lysis syndrome is not known (Hsu et al, 2004). The criteria for definition of tumour lysis syndrome proposed by Cairo and Bishop (2004) were met in this case. Acute tumour lysis syndrome is commonly associated with highly aggressive, bulky lymphoma with high tumour burden. Therefore an aggressive rapidly proliferating lymphoma was initially suspected based on the presentation. In contrast, the final diagnosis was follicular lymphoma, which is considered to be an indolent B-cell lymphoproliferative disorder. The prognosis of follicular lymphoma remains mixed; some patients are asymptomatic for many years, while others may rapidly present with a life-threatening
disease. The patient was classified as low risk of death in follicular lymphoma by the follicular lymphoma international prognostic index (FLIPI) or FLIPI 2 (Federico et al, 2009) because she had one adverse factor (FLIPI: stage IV, FLIPI 2: bone marrow involvement). Meanwhile, the elevated level of serumsoluble interleukin-2 receptor (sIL-2R) found in this patient suggests poor prognosis. A high sIL-2R level has been associated with poor prognosis in non-Hodgkin lymphoma (Jo et al, 2010). Yoshizato et al (2013) showed that sIL-2R correlated with clinical stages, numbers of nodal regions, clinical outcomes and response to treatment. To the best of the authors’ knowledge, this is the first case reporting spontaneous tumour lysis syndrome in a patient with follicular lymphoma. The aetiology of spontaneous tumour lysis syndrome is
Case Report
A 56-year-old woman with no specific past medical history except hypertension was admitted to the authors’ centre with a 3-week history of fatigue, lethargy, decreased appetite and vague abdominal pain. She had lost 5 kg during this period. Physical examination revealed stable vital signs, enlargement of neck and axillary lymph nodes, and splenomegaly. Computed tomography scan showed systemic lymphadenopathy and a 5.8 cm adrenal homogenous mass. 18F-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography showed 18F-fluoro-2-deoxy-D-glucose uptake in multiple lymph nodes and the adrenal mass (Figure 1). Laboratory work showed severe metabolic derangements: serum urea nitrogen 68 mg/dl (normal 6–21 mg/dl), potassium 6.2 mmol/litre (normal 3.6–5.2 mmol/litre), creatinine 3.4 mg/dl (normal 0.6–1.1 mg/dl), lactate dehydrogenase 150 IU/litre (normal 122–222 IU/litre), uric acid 12.5 mg/dl (normal 2.7–6.1 mg/dl), ionized calcium 3.71 mg/ dl (normal 4.80–5.70 mg/dl) and phosphate 6.9 mg/dl (normal 2.5–4.5 mg/dl). An arterial blood gas analysis showed a pH of 7.19, PCO2 2.3 mmHg, PO2 17.0 mmHg and bicarbonate 5.5 mmol/litre. A presumptive diagnosis of lymphoma with spontaneous tumour lysis syndrome was made. After aggressive treatment with intravenous hydration and furosemide, laboratory abnormalities dramatically improved over the next 24 hours. An axillary lymph node biopsy exhibited follicular lymphoma, grade 3, ultimately found to be stage IV (Figure 2). There was also follicular lymphoma in the bone marrow. Additional laboratory data included beta-2 microglobulin 1.4 mg/litre (normal 0.8–2.2 mg/litre) and serum-soluble interleukin-2 receptor (sIL-2R) level 2180 U/ml (range 195–12 520 U/ml). The patient subsequently underwent chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). There was no recurrence of tumour lysis syndrome after chemotherapy. Metabolic complete remission was achieved after two cycles of R-CHOP, and the patient remained progression free for 28 months after completing six cycles.
© 2015 MA Healthcare Ltd
Introduction
British Journal of Hospital Medicine, March 2015, Vol 76, No 3
itish Journal of Hospital Medicine. Downloaded from magonlinelibrary.com by 139.080.123.044 on July 29, 2015. For personal use only. No other uses without permission. . All rights reserve
Case Report indolent malignancy should also be suspected in clinical cases of spontaneous tumour lysis syndrome. BJHM This research was supported by a Chung-Ang University Research Grant. Professor Kim receives institutional research support from Chung-Ang University.
Figure 1. a. Initial computed tomography scan showing a right adrenal homogeneous solid mass (5.8 cm, arrow) and multiple lymph node enlargements in the left para-aortic space (arrow head). b. Initial 18F-fluoro-2-deoxy-D-glucose positron emission tomography scan showing hypermetabolic lesion in right adrenal mass (maximum SUV 14.9).
© 2015 MA Healthcare Ltd
Figure 2. Microscopic finding of follicular lymphoma. a. The lymph node shows atypical follicular structures without germinal centre (haematoxylin and eosin stain x100). b. Immunostain for Bcl-2 shows diffuse, strong positive reaction in the follicular structures (x100).
unclear. Considering conventional risk factors for tumour lysis syndrome, the burden of tumour may have been an important factor in this case. The possibility of a histological transformation to a high grade lymphoma should be considered. The annual risk of transformation of follicular lymphoma is 3% continuing without plateau beyond 15 years (Al-Tourah et al, 2008). While node biopsy showed only follicular lymphoma, it is reasonable to assume that there could have been unseen partial transformation. However, this seems unlikely because of several factors: normal plasma lactate dehydrogenase and ionized calcium levels, no evidence of transformation on bone marrow examination, and the benign clinical course, which is uncommon in highgrade transformation.
Conclusions
This article reports an unusual case in which spontaneous tumour lysis syndrome was the initial presentation of follicular lymphoma. It should be noted that spontaneous tumour lysis syndrome may happen in follicular lymphoma with a large tumour volume and low risk prognostic factors. Although uncommon,
Al-Tourah AJ, Gill KK, Chhanabhai M et al (2008) Population-based analysis of incidence and outcome of transformed non-Hodgkin's lymphoma. J Clin Oncol 26: 5165–9 (doi: 10.1200/jco.2008.16.0283) Cairo MS, Bishop M (2004) Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127: 3–11 (doi: 10.1111/j.1365-2141.2004.05094) Coiffier B, Altman A, Pui CH, Younes A, Cairo MS (2008) Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26: 2767–78 (doi: 10.1200/jco.2007.15.0177) Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, Schreiber MJ (2004) Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med 116: 546–54 (doi: 10.1016/j.amjmed.2003.09.045) Drakos P, Bar-Ziv J, Catane R (1994) Tumor lysis syndrome in nonhematologic malignancies. Report of a case and review of the literature. Am J Clin Oncol 17: 502–5 (doi: 10.1097/00000421199412000-00010) Federico M, Bellei M, Marcheselli L et al (2009) Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 27: 4555–62 (doi: 10.1200/ jco.2008.21.3991) Hsu HH, Chan YL, Huang CC (2004) Acute spontaneous tumor lysis presenting with hyperuricemic acute renal failure: clinical features and therapeutic approach. J Nephrol 17: 50–6 (doi: 10.1007/bf02983533) Jasek AM, Day HJ (1994) Acute spontaneous tumor lysis syndrome. Am J Hematol 47: 129–31 (doi: 10.1002/ajh.2830470212) Jo SA, Hwang SH, Chang CL et al (2010) Clinical relevance of elevated levels of serum soluble interleukin-2 receptor alpha (sIL-2Ralpha) in patients with non-Hodgkin's lymphoma. Korean J Lab Med 30: 600–5 (doi: 10.3343/ kjlm.2010.30.6.600) Yoshizato T, Nannya Y, Imai Y, Ichikawa M, Kurokawa M (2013) Clinical significance of serum-soluble interleukin-2 receptor in patients with follicular lymphoma. Clin Lymphoma Myeloma Leuk 13: 410–16 (doi: 10.1016/j. clml.2013.03.014)
LEARNING POINTS n Biochemical findings which indicate tumour lysis syndrome are hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia and/or azotaemia secondary to a rapid breakdown of tumour cells. n Acute tumour lysis syndrome is commonly associated with highly aggressive, bulky lymphoma with high tumour burden. n Although rare and low risk, indolent follicular lymphoma is a clinically relevant cause of spontaneous tumour lysis syndrome.
British Journal of Hospital Medicine, March 2015, Vol 76, No 3
173
itish Journal of Hospital Medicine. Downloaded from magonlinelibrary.com by 139.080.123.044 on July 29, 2015. For personal use only. No other uses without permission. . All rights reserve
